Kinases are essential cellular signaling molecules. Mutations in kinases can lead to diseases or conditions including immunodeficiencies, cancers, cardiovascular diseases and endocrine disorders, such as Parkinson's disease, metabolic diseases, tumorigenesis, Alzheimer's disease, heart disease, diabetes, neurodegeneration, inflammation, kidney disease, atherosclerosis and airway disease.
Cancers result from deregulated signaling pathways that mediate cell growth and programmed cell death (apoptosis). Protein kinases are a large family of proteins that play an important role in signaling pathways that regulate a number of different cellular functions, such as cell growth, differentiation, and death.
Hyperactivity of protein kinases is implicated in a variety of human cancers. For example, the Akt2 kinase has been found to be over-expressed in ovarian tumors (J. Q. Cheung et al., Proc. Natl. Acad. Sci. U.S.A. 89: 9267-9271 (1992)) and pancreatic cancers (J. Q. Cheung et al., Proc. Natl. Acad. Sci. U.S.A. 93: 3636-3641 (1996)), and the Akt3 kinase was found to be over-expressed in breast and prostate cancer cell lines (Nakatani et al., J. Biol. Chem. 274: 21528-21532 (1999)).
Various protein kinase inhibitors have been shown to effectively treat certain cancers. For example, Gleevec™ (imantinib, Novartis), can be used to treat chronic myeloid leukemia (CML) (Kumar et al.), and a Raf kinase inhibitor (BAY-43-9006) has been evaluated for treating solid tumors and myeloid leukemia (WO 2004/022562).
Tyrosine kinase is a group of enzymes for catalyzing phosphorylation of protein tyrosine residues, and it plays a critical role in endocellular signal transduction. Tyrosine kinase participates in the regulation of normal cells, signal transmission and development, as well as associates with proliferation, differentiation, migration and apoptosis of tumor cell. Dysfunction of tyrosine kinase can cause the disorder of cell proliferation, leading to the formation of tumor eventually.
Tyrosine kinases for many receptors are involved in the formation of tumor, the reasons of which include gene mutation, chromosome translocation or kinase over-expression.
Tyrosine kinase inhibitors are designed according to the structures of the protein tyrosine kinases, and most of them belong to competitive inhibitors of ATP (adenosine triphosphate). These inhibitors act on the intracellular kinase region of tyrosine protein kinase, so as to inherently block the downstream signal transduction mediated by tyrosine kinase, and therefore inhibit the growth, angiogenesis and metastasis of tumor.
Vandetanib is a synthesized aniline-quinazoline compound, which can act on tyrosine kinases for VEGFR, EGFR and RET of the tumor cells simultaneously, and also can selectively inhibit other tyrosine kinases as well as serine/threonine kinases.
Therefore, target drugs that can inhibit the protein kinase represent a new generation of chemotherapeutic agents for the specific molecule objects. And they have the potential to provide greater efficacy in the treatment of various cancers with fewer side effects than conventional chemotherapeutic agents.